The current licensed vaccine against smallpox, Dryvax, generates strong and long-lasting immunity. However, serious side-effects are associated with Dryvax immunization. Furthermore, in the current environment of a naive population and with an increasing number of immunocompromised people, use of the replication-competent Dryvax immunogen may be considered ill-advised. In the current political situations, the threat also exists of a weaponized form of the smallpox virus. The goal of these studies is to evaluate the efficacy of the non-replicating vaccinia virus MVA (modified vaccinia Ankara) in protecting against challenge with replication-competent vaccinia virus. The correlates of immunity induced by Dryvax immunization have not been identified. Therefore, these studies will evaluate the contributions of CD4+ T cells, CD8+ T cells, and antibody to anti-vaccinia virus immunity.